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Unit 15: Gastroenteritis and Hepatitis Pathogens and Enteroviruses

Head:
Claus-Thomas Bock
Deputy:
Sabine Diedrich

The unit analyses human pathogenic, primarily fecal-orally transmitted pathogens of viral gastroenteritides (calici- and rotaviruses), hepatitis viruses (HEV, as well as HBV and HCV) and enteroviruses in terms of properties and variability for the purpose of monitoring virus circulation by means of molecular epidemiological methods. The investigations are carried out in close co-operation with national and international networks.

The unit hosts the National Reference Centre as well as the Regional WHO/EURO Reference Centre for Poliomyelitis and Enteroviruses (NRC PE) and since 2010 the Secretariat of the National Committee for Polio Eradication in Germany as well as the Consultant Laboratory for Noroviruses and the Consultant Laboratory for Rotaviruses. The main tasks of the NRC PE and the CLs for Noroviruses and Rotaviruses include the surveillance of circulating viruses, the analysis of pathogen variability, special diagnostics (e.g. fine typing), quality assurance, the surveillance of enteroviruses as well as analyses of outbreaks (in co-operation with department 3). These laboratories carry out consulting, diagnostics and scientific studies within the framework of their remit.

The work on hepatitis viruses focuses on the carrying out of special diagnostics, including investigations on pathogen properties, antiviral resistance as well as fine and genotyping. The goal is to record the occurrence and dynamics of hepatitis viruses circulating in Germany, in particular hepatitis E viruses (HEV), to analyse them in molecular epidemiological terms and to characterise the risk potential emerging from wild type viruses and virus variants.

The Consultant Laboratories for Noroviruses and Rotaviruses are accredited in accordance with DIN EN ISO 15189 and DIN EN ISO/IEC17025 on the basis of DIN EN ISO 9001 (DAkkS).

Tasks

Viral gastroenteritides

Consultant Laboratory for Noroviruses

  • Molecular epidemiological analyses concerning the circulation of noroviruses and other gastroenteritis viruses (pathogen variability, transmission)
  • Investigations on the recombination of viral RNA
  • Pathogenesis of the norovirus infection
  • Co-operation within the European “NoroNet” for the surveillance of norovirus circulation in Europe

Consultant Laboratory for Rotaviruses

  • Molecular detection of rotaviruses of Group A, B and C
  • Molecular epidemiological investigations on the circulation of rotavirus A (G/P typing)
  • Differentiation of wild and vaccination viruses

Poliomyelitis and enteroviruses

National Reference Centre for Poliomyelitis and Enteroviruses (NRC PE) and Regional Reference Laboratory of the WHO/EURO for Poliomyelitis

  • Detection of enteroviruses in patients with aseptic meningitis/encephalitis and acute flaccid paralyses
  • Molecular-epidemiological analysis of selected picornavirus serotypes
  • Studies on population immunity, in particular to poliomyelitis
  • Intratypic differentiation of poliovirus isolates using molecular methods (PCR, sequencing in different genome regions)
  • Support of European countries in the diagnostic clarification of selected AFP cases (cultivation, typing and sequencing)

Secretariat of the National Commission for Polio Eradication in Germany

  • Surveillance of polio- free status of Germany within the context of the WHO programme for the eradication of poliomyelitis (National Enterovirus Surveillance)
  • Co-ordination of the laboratory network for enterovirus diagnostics in Germany (LaNED)
  • Laboratory containment of polioviruses

Viral hepatitides

Laboratory for Hepatitis Virus Infections

  • Molecular epidemiological investigations on the circulation of hepatitis viruses (HEV, HBV and HCV)
  • Variability of hepatitis viruses (HEV, HBV) in connection with persistence and therapy resistance
  • Molecular mechanisms of cellular interference mechanisms and pathogenesis of hepatitis viruses (HEV, HBV)
  • Prevalence, pathogenicity and clinical relevance of nonB-nonE hepatitis viruses (e.g. HAV, TTV, parvovirus B19 (B19V) and others)

Date: 29.12.2015

Publications

  • Ratsch BA, Bock CT (2012): Viral evolution in chronic hepatitis B: a branched way to HBeAg seroconversion and disease progression?.
    Gut: Epub Dec 15. doi: 10.1136/gutjnl-2012-303681.

  • Wedemeyer H, Yurdaydin C, Dalekos GN, Erhardt A, Çakaloğlu Y, Değertekin H, Gürel S, Zeuzem S, Zachou K, Bozkaya H, Koch A, Bock CT et al., HIDIT Study Group (2011): Peginterferon plus adefovir versus either drug alone for hepatitis delta.
    N. Engl. J. Med. 364 (4): 322-331. more

  • Schorn R, Höhne M, Meerbach A, Bossart W, Wüthrich RP, Schreier E, Müller NJ, Fehr T (2010): Chronic norovirus infection after kidney transplantation: molecular evidence for immune-driven viral evolution.
    Clin. Infect. Dis. 51 (3): 307-314. more

  • Bock CT, Klingel K, Kandolf R (2010): Human parvovirus B19-associated myocarditis. (Letter).
    N. Engl. J. Med. 362 (13): 1248-1249.

  • Mirand A, Schuffenecker I, Henquell C, Billaud G, Jugie G, Falcon D, Mahul A, Archimbaud C, Terletskaia Ladwig E, Diedrich S et al. (2010): Phylogenetic evidence for a recent spread of two populations of human enterovirus 71 in European countries.
    J. Gen. Virol. 91 (9): 2263-2277. Epub May 26. more

  • Mikula C, Springer B, Reichart S, Bierbacher K, Lichtenschopf A, Höhne M (2010): Sapovirus in adults in rehabilitation center, upper Austria.
    Emerg. Infect. Dis. 16 (7): 1186-1187.

  • Jaroszewicz J, Serrano BC, Wursthorn K, Deterding K, Schlue J, Raupach R, Flisiak R, Bock CT et al. (2010): Hepatitis B surface antigen (HBsAg) levels in the natural history of hepatitis B virus (HBV)-infection: a European perspective.
    J. Hepatol. 52 (4): 514-522. Epub Feb 13. more

  • Mederacke I, Bremer B, Heidrich B, Kirschner J, Deterding K, Bock CT et al. (2010): Establishment of a novel quantitative hepatitis D virus (HDV) RNA assay using the Cobas TaqMan platform to study HDV RNA kinetics.
    J. Clin. Microbiol. 48 (6): 2022-2029. Epub Mar 29. more

  • Wadl M, Scherer K, Nielsen S, Diedrich S, Ellerbroek L, Frank C, Gatzer R, Höhne M, Johne R, Klein G, Koch J, Schulenburg J, Thielbein U, Stark K, Bernard H (2010): Food-borne norovirus-outbreak at a military base, Germany, 2009.
    BMC Infect. Dis. 10: 30. doi:10.1186/1471-2334-10-30. more

  • Diedrich S, Weinbrecht A, Schreier E (2009): Seroprevalence and molecular epidemiology of enterovirus 71 in Germany.
    Arch. Virol. 154 (7): 1139-1142. Epub Jun 9. more

  • Siebenga J, Vennema H, Zheng DP, Vinjé J, Lee BE, Pang XL, Ho EC, Lim W, Choudekar A, Broor S, Halperin T, Rasool NB, Hewitt J, Greening GE, Jin M, Duan ZJ, Lucero Y, O'Ryan M, Höhne M, Schreier E et al. (2009): Norovirus Illness Is a Global Problem: Emergence and Spread of Norovirus GII.4 Variants, 2001-2007.
    J. Infect. Dis. 200 (5): 802-812. more

Laboratory for Hepatitis Virus Infections

Head:
Claus-Thomas Bock

The hepatitis E virus (HEV) infection is spread all over the wold and constitutes a major health issue more particularly in developing countries. The HEV infection involves large outbreaks in India, Asia and Africa and is the most frequent cause for acute hepatitides around the world. In clinical terms the HEV infection has mostly an asymptomatic course, but can also trigger fulminant hepatic failure. HEV is transmitted fecal-orally and has so far been considered as a travel-associated disease; however, transmissions by blood transfusion have been described, too. During the past years there has been a constant increase in notified HEV cases in Germany, with a doubling between 2009 and 2010. This involved primarily autochthonous infections without travel anamnesis. The mortality rate of HEV infection is 2 % but can amount to up to 25 % for pregnant women. More recently an increase in chronic HEV infections was observed, in particular for immunosuppressed patients after organ transplantation and for HIV-infected patients in Germany. The chronic HEV infection leads more frequently to severe liver inflammations, such as cirrhosis. Since current HEV detection systems are limited and molecular mechanisms which can contribute to different clinical courses and to the chronification are still unclear, goals include the optimisation of serological and molecular detection methods, the determination of pathogen variability and the characterisation of chronification mechanisms by means of molecular virological methods.

The human hepatitis B Virus (HBV), a small, strictly hepatotrophic DNA virus, is a member of the family of hepadnaviruses, which are different from all known DNA viruses because of an extraordinary replication mechanism, similar to retroviruses through a reverse transcription. HBV causes hepatitis B, one of the most important infection diseases with severe consequences. According to estimates by WHO, approximately 2 billion people (around 35 % of the world population) have currently had a contact with HBV. After the infection, hepatitis B mostly occurs in an acute manner and then heals. Depending on the immune status of the HBV infected and other factors (e.g. virus mutants), the HBV infection can transform in approximately 10% of the acute cases into a chronic form. In global terms a chronic hepatitis B is assumed for approximately 360 million people (WHO 2010). HBV is primarily endemic in developing countries such as South East Asia, Africa and South America with partly > 8 % virus carrier rates. Recent surveys showed for Germany a hepatitis B virus carrier rate of 0.4 % - 0.8 % (~500,000 persons, RKI 2010). The prevalence rate of HBV depends not only on the geographical distribution but also on the risk behaviour (e.g. IV drug consumption with non-sterile injection utensils). The clinical course of hepatitis B is highly variable and reaches from asymptomatic, inapparent to fulminant and severe inflammations of the liver, such as liver cirrhosis and hepatocellular carcinoma (HCC). Every year about 1 million people die from the consequences of hepatitis, mostly by HBV induced liver cirrhosis and HCC. The diagnostics of acute and chronic hepatitis B is carried out virologically-serologically as well as molecular biologically according to the guidelines on prophylaxis, diagnostics and therapy of the hepatitis B virus infection. Special investigations, such as the detection of escape and resistance mutants as well as genotyping can be carried out in especially identified laboratories. A vaccination prophylaxis against HBV is recommended by the Standing Committee on Vaccination (Stiko) in Germany for children and adolescents.

The hepatitis C virus (HCV), a hepatotrophic single strand (+) RNA virus, belongs to the family of flaviviruses and was described for the first time in 1989. As opposed to hepatitis B, hepatitis C is chronic in more than 80 % of the infected patients. At present approximately 170 million people around the world (~ 3 % of the world population) are chronically infected. The chronic form of hepatitis C is, in addition to the chronic hepatitis B, responsible for the majority of all cases of liver cirrhosis (27 %) and liver cell carcinoma (25 %) around the world. The HCV infection occurs geographically with a different prevalence. More than 70% of the virus carriers are in Asia and Africa. It is assumed that there are some 9 million chronically infected HCV patients in Europe. In Germany, approximately 0.6 % (ca. 500,000 persons) (WHO, RKI 2009) are chronically infected with HCV.

The highly sensitive molecular hepatitis virus diagnostics have gained in importance during the past years, in particular for the monitoring of the antiviral therapy of chronic hepatitis. Specialised molecular detection methods serve for the qualitative and quantitative detection of hepatitis virus genomes (DNA and RNA), viral replication intermediates (e.g. HBV cccDNA) and the detection of virus mutants. Apart from the determination of the virus load, the detection of the occurrence of therapy- resistant mutants plays a major role in view of the optimisation of an antiviral therapy strategy. Moreover, the genotyping of HEV, HBV and HCV is of major significance for the classification of the therapy response to be expected, susceptibility vis a vis an antiviral substance and virulence. Consequently, modern molecular detection methods (real-time PCR, sequencing, RFLP-PCR, phylogenetic and mutation analyses) and their further development are amongst the tasks of the Hepatitis Laboratory.

Translational research activities of the Hepatitis Laboratory target scientific issues relating to the clinical relevance and sensitive detection of virus mutants (therapy response and chronification, in particular for HEV) as well as investigations on the inter- and intramolecular virus-host interactions, in particular the influence of hepatitis viruses on the inflammatory signal transduction. The scientific activities are carried out in close networking with hospitals and universities.

Service offering

• Molecular detection of HEV-RNA, HBV-DNA, HCV-RNA, HDV-RNA by means of nucleic acid amplification techniques (PCR) (other hepatitis viruses on request, e.g. HAV, TTV, B19V)
• Molecular genetic fine characterisation of virus variants (genotyping)
• Antiviral resistance analysis of HBV with consulting on request
• Further special investigations on request (mutation analyses, analyses of cccDNA)

Date: 01.02.2013

Publications

  • Ratsch BA, Bock CT (2012): Viral evolution in chronic hepatitis B: a branched way to HBeAg seroconversion and disease progression?.
    Gut: Epub Dec 15. doi: 10.1136/gutjnl-2012-303681.

  • Wedemeyer H, Yurdaydin C, Dalekos GN, Erhardt A, Çakaloğlu Y, Değertekin H, Gürel S, Zeuzem S, Zachou K, Bozkaya H, Koch A, Bock CT et al., HIDIT Study Group (2011): Peginterferon plus adefovir versus either drug alone for hepatitis delta.
    N. Engl. J. Med. 364 (4): 322-331. more

  • Jaroszewicz J, Ho H, Markova A, Deterding K, Wursthorn K, Schulz S, Bock CT et al. (2011): Hepatitis B surface antigen (HBsAg) decrease and serum interferon-inducible protein-10 levels as predictive markers for HBsAg loss during treatment with nucleoside/nucleotide analogues.
    Antivir. Ther. 16 (6): 915–924. more

  • Tong HV, Toan NL, Song le H, Ouf EA, Bock CT et al. (2011): Ficolin-2 Levels and FCN2 Haplotypes Influence Hepatitis B Infection Outcome in Vietnamese Patients.
    PLoS One 6 (11): e28113. Epub Nov 22. more

  • Mederacke I, Bremer B, Heidrich B, Kirschner J, Deterding K, Bock CT et al. (2010): Establishment of a novel quantitative hepatitis D virus (HDV) RNA assay using the Cobas TaqMan platform to study HDV RNA kinetics.
    J. Clin. Microbiol. 48 (6): 2022-2029. Epub Mar 29. more

  • Jaroszewicz J, Serrano BC, Wursthorn K, Deterding K, Schlue J, Raupach R, Flisiak R, Bock CT et al. (2010): Hepatitis B surface antigen (HBsAg) levels in the natural history of hepatitis B virus (HBV)-infection: a European perspective.
    J. Hepatol. 52 (4): 514-522. Epub Feb 13. more

  • Bock CT, Klingel K, Kandolf R (2010): Human parvovirus B19-associated myocarditis. (Letter).
    N. Engl. J. Med. 362 (13): 1248-1249.

  • Koeberlein B, zur Hausen A, Bektas N, Zentgraf H, Chin R, Linh Toan N, Kandolf R, Torresi J, Bock CT (2010): Hepatitis B virus overexpresses suppressor of cytokine signaling-3 (SOCS3) thereby contributing to severity of inflammation in the liver.
    Virus Res. 148 (1-2): 51-59. Epub 2009 Dec 17. more

  • Chin R, Nachbur U, Earnest-Silveira L, Bankovacki A, Koeberlein B, Zentgraf H, Bock CT, Silke J, Torresi J (2010): Dysregulation of hepatocyte cell cycle and cell viability by hepatitis B virus.
    Virus Res. 147 (1): 7-16. more

  • Bock CT, Toan NL, Koeberlein B, Song Le H, Chin R, Zentgraf H, Kandolf R, Torresi J (2008): Subcelluar mislocalization of mutant hepatitis B X-proteins contributes to modulation of STAT/SOCS signaling in hepatocellular carcinoma.
    Intervirology 51: 432-443. more

  • Deterding K, Constantinescu I, Nedelcu FD, Gervain J, Nĕmeček V, Srtunecky O, Vince A, Grgurevic I, Bielawski KP, Zalewska M, Bock CT, et al. (2008): Prevalence of HBV-Genotypes in Central and Eastern Europe.
    J. Med. Virol. 80: 1707-1711. more

  • Chin R, Earnest-Silveira L, Koeberlein B, Franz S, Zentgraf H, Bowden S, Bock CT, Torresi J (2008): Failure of lamivudine to reverse HBV associated changes in ERK, Akt and cell cycle regulatory proteins.
    Antivir. Ther. 13: 221-230. more

  • Toan NL, Song le H, Kremsner PG, Duy DN, Binh VQ, Koeberlein B, Kaiser S, Kandolf R, Torresi J, Bock CT (2006): Impact of the hepatitis B virus genotype and genotype-mixtures on the course of liver disease in Vietnam.
    Hepatology 43: 1375-1384. more

  • Bock CT (2007): Molekulare Pathogenese des Hepatitis B Virus.
    In: Tillmann HL (eds), Handbuch Hepatitis B-Diagnostik, Verlauf, Therapie. Bremen, London, Boston: Uni-Med Verlag AG, pp. 42-45.

  • Bock CT (2007): Hepatitis B Virus-Mutanten.
    In: Tillmann HL (eds), Handbuch Hepatitis B-Diagnostik, Verlauf, Therapie. Bremen, London, Boston: Uni-Med Verlag AG, pp. 88-92.